Tumor microenvironment-driven mechanisms of photodynamic therapy resistance and emerging targeted combination...

The tumor microenvironment (TME), characterised by immunosuppression, hypoxia, acidity, and high interstitial pressure, creates a unique microenvironment that facilitates tumorigenesis and treatment resistance. Photodynamic therapy (PDT) has emerged as a promising and effective modality for cancer treatment. Beyond the intrinsic parameters of PDT, increasing evidence indicates that the TME critically regulates therapeutic efficacy and contributes to the development of acquired resistance. Targeted modulation of the TME to enhance PDT outcomes and overcome resistance has therefore become an attractive therapeutic strategy. This review systematically summarizes the effects of key TME characteristics-including acidic conditions, immunosuppressive states, hypoxia, and elevated interstitial fluid pressure on PDT efficacy and the mechanisms underlying PDT-acquired resistance. Furthermore, current combination strategies aimed at remodeling the TME to improve PDT performance are comprehensively discussed, with particular emphasis on biomaterial-based therapeutic approaches. Finally, in view of the limitations of existing combination therapies, future research directions are highlighted, focusing on a deeper understanding of the dynamic evolution of the TME and the development of intelligent nanomaterial-based targeted delivery platforms to enable precise and personalized PDT.